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At least 19 recordsLinked to original sources

PubMed2001

Stereoselective pharmacokinetics of ketamine: R(-)-ketamine inhibits the elimination of S(+)-ketamine.

OBJECTIVE: We investigated the pharmacokinetics of ketamine with special regard to enantiomer-specific differences. METHODS: Ten healthy young male volunteers (mean age, 28 +/- 4 years; mean weight, 79 +/- 11 kg) received racemic ketamine and S(+)-ketamine in a randomized double-blind crossover study. Drugs were administered by a computer-controlled device. Two infusion cycles with linearly increasing targets [slope, 0.1 microg x ml(-1) x min(-1) for S(+)-ketamine and 0.2 microg x ml(-1) x min(-1) for racemic ketamine] were administered. Concentrations of the ketamine enantiomers were determined from arterial blood, and pharmacokinetic parameters were estimated with a 2- and 3-compartment model. RESULTS: The total doses needed to reach defined end points were 271 +/- 80 mg and 409 +/- 75 mg for S(+)-ketamine and racemic ketamine, respectively (P <.05). S(+)-ketamine showed a significantly higher clearance (26.3 +/- 3.5 ml x kg(-1) x min(-1)) compared with racemic ketamine (14.8 +/- 1.7 ml x kg(-1) x min(-1); P <.05) and R(-)-ketamine (13.8 +/- 1.3 ml x kg(-1) x min(-1); P <.05). Furthermore, the clearance of the S (+)-ketamine was smaller in the racemate (18.5 +/- 0.7 ml x kg(-1) x min(-1); P <.05) than for the pure isomer. CONCLUSIONS: These results demonstrate that R(-)-ketamine inhibits the elimination of S(+)-ketamine.

Adult↗

PubMedDate not supplied

Comparison of anesthetic and cardiorespiratory effects of diazepam-butorphanol-ketamine, acepromazine-butorphanol-ketamine, and xylazine-butorphanol-ketamine in ferrets.

Ten ferrets were used in a crossover study to determine the sedative effects of intramuscularly administered diazepam (3 mg/kg body weight)-butorphanol (0.2 mg/kg body weight)-ketamine (15 mg/kg body weight); acepromazine (0.1 mg/kg body weight)-butorphanol (0.2 mg/kg body weight)-ketamine (15 mg/kg body weight); and xylazine (2 mg/kg body weight)-butorphanol (0.2 mg/kg body weight)-ketamine (15 mg/kg body weight). All of the ferrets became laterally recumbent following the administration of each drug combination. The xylazine-butorphanol-ketamine combination induced significantly longer (p less than 0.05) durations of tail-clamp analgesia (mean+/-standard deviation [SD], 81.0+/-19.1 min versus 20.5+/-25.4 min and 30.0+/-26.9 min), dorsal recumbency (mean+/-SD, 94.6+/-13.6 min versus 75. 6+/-34.7 min and 55.2+24.8 min), and muscle relaxation suitable for endotracheal intubation (mean+/-SD, 67.1+/-23.0 min versus 7.0+/-22.1 min and 9.5+/-15.4 min) than the diazepam-butorphanol-ketamine and acepromazine-butorphanol-ketamine combinations, respectively. The recovery time from dorsal recumbency to standing was not significantly different among the three treatment groups. The heart rate was significantly lower in the xylazine-butorphanol-ketamine group; however, systolic blood pressure was not significantly different among the treatment groups. Ventilatory function was more depressed in the diazepam-butorphanol-ketamine and xylazine-butorphanol-ketamine groups than in the acepromazine-butorphanol-ketamine group. A period (approximately 45 minutes) of hypoxia was observed in the xylazine-butorphanol-ketamine-treated ferret. Of the three combinations evaluated in ferrets, xylazine-butorphanol-ketamine was concluded to be the most effective anesthetic combination. However, hypoxemia and ventricular arrhythmias were observed in the xylazine-butorphanol-ketamine-treated ferrets, so the effectiveness of the xylazine-butorphanol-ketamine combination should be weighed against its cardiorespiratory side effects.

Acepromazine↗

PubMed2007

Stereoselective pharmacokinetics of ketamine and norketamine after racemic ketamine or S-ketamine administration during isoflurane anaesthesia in Shetland ponies.

BACKGROUND: The arterial pharmacokinetics of ketamine and norketamine enantiomers after racemic ketamine or S-ketamine i.v. administration were evaluated in seven gelding ponies in a crossover study (2-month interval). METHODS: Anaesthesia was induced with isoflurane in oxygen via a face-mask and then maintained at each pony's individual MAC. Racemic ketamine (2.2 mg kg(-1)) or S-ketamine (1.1 mg kg(-1)) was injected in the right jugular vein. Blood samples were collected from the right carotid artery before and at 1, 2, 4, 8, 16, 32, 64, and 128 min after ketamine administration. Ketamine and norketamine enantiomer plasma concentrations were determined by capillary electrophoresis. Individual R-ketamine and S-ketamine concentration vs time curves were analysed by non-linear least square regression two-compartment model analysis using PCNonlin. Plasma disposition curves for R-norketamine and S-norketamine were described by estimating AUC, C(max), and T(max). Pulse rate (PR), respiratory rate (R(f)), tidal volume (V(T)), minute volume ventilation (V(E)), end-tidal partial pressure of carbon dioxide (PE'(CO(2))), and mean arterial blood pressure (MAP) were also evaluated. RESULTS: The pharmacokinetic parameters of S- and R-ketamine administered in the racemic mixture or S-ketamine administered separately did not differ significantly. Statistically significant higher AUC and C(max) were found for S-norketamine compared with R-norketamine in the racemic group. Overall, R(f), V(E), PE'(CO(2)), and MAP were significantly higher in the racemic group, whereas PR was higher in the S-ketamine group. CONCLUSIONS: Norketamine enantiomers showed different pharmacokinetic profiles after single i.v. administration of racemic ketamine in ponies anaesthetised with isoflurane in oxygen (1 MAC). Cardiopulmonary variables require further investigation.

Anesthesia, General↗

PubMed1997

[Endocrine reactions, circulatory and resuscitation behavior in ketamine-midazolam anesthesia. A comparative study of ketamine racemate vs. (S)-ketamine in knee surgery].

UNLABELLED: Clinically used ketamine is a racemic mixture of two isomers, (S)- and (R)-ketamine, in equal amounts. Previous investigations showed the anaesthetic potency of (S)-ketamine to be three times higher than that of (R)-ketamine. The aim of this study was to compare the effects of (S)-ketamine/midazolam and racemic ketamine/midazolam on endocrine and cardiovascular parameters, recovery, and side effects in unpremedicated patients during knee surgery. METHODS: 41 patients scheduled for elective knee surgery were investigated in a prospective, double-blind, and randomised design. For induction of intravenous anesthesia, patients received 0.1 mg/kg midazolam, 0.003 mg/kg atropine, 1 mg/kg (S)-ketamine or 2 mg/kg racemic ketamine, respectively. For tracheal intubation, 1 mg vecuronium and 1.5 mg/kg suxamethonium were injected. After intubation and relaxation with a total dose of 0.1 mg/kg vecuronium, a continuous infusion of 0.5 mg/kg/h (S)- or 1 mg/kg/h racemic ketamine was administered throughout the surgery. In addition, 0.05 mg/kg/h midazolam was infused continuously in both groups throughout surgery. Ventilation was performed with N2O/O2 (FiO2 0.3). Blood samples were taken using a central venous line five times before induction as well as during and after surgery for analysis of adrenaline, noradrenaline (by high-pressure liquid chromatography with electrochemical detection), anti-diuretic hormone (ADH), adrenocorticotropic hormone (ACTH), and cortisol (by radioimmunoassay). In addition, systolic and diastolic arterial pressure (SAP, DAP), heart rate (HR), and arterial oxygen saturation were measured. The time intervals between the end of ketamine and midazolam infusion and the return of consciousness and orientation were recorded. The incidence and quality of dreams and other side effects were reported by the patients. RESULTS: Biometric data of the groups were comparable. Plasma adrenaline and noradrenaline did not change significantly during anaesthesia. ADH increased significantly (p < 0.05) after skin incision in both groups.

Adolescent↗

PubMed1985

Evaluation of ketamine, ketamine-xylazine and ketamine-diazepam anesthesia in the ferret.

Ketamine, ketamine-xylazine, and ketamine-diazepam were evaluated clinically in 15 ferrets, and safe dosage was determined for each. All of the three regimens provided excellent immobilization. However, muscle rigidity and incomplete analgesia were noted in ketamine alone and in ketamine-diazepam respectively. It was concluded that 25 mg/kg ketamine and 2 mg/kg xylazine intramuscularly provided acceptable analgesia, muscle relaxation, duration and smooth recovery, although cardiac arrhythmias were a concern and require careful observation.

Anesthesia, General↗

PubMed1996

Ketamine and its use in the pig. Recommendations of the Consensus meeting on Ketamine Anaesthesia in Pigs, Bergen 1994. Ketamine Consensus Working Group.

Ketamine, when used as a mono-anaesthetic, does not appear to induce surgical anaesthesia in the pig. The addition of other drugs such as opioids, benzodiazepines and alpha 2-adrenergic agonists deepens anaesthesia and enables major surgery to be performed. A decision-tree for the rational use of ketamine for both short and long-term anaesthesia in the pig under three different levels of procedure severity is presented.

Anesthesia↗

PubMed1992

[Ketamine racemate or S-(+)-ketamine and midazolam. The effect on vigilance, efficacy and subjective findings].

Ketamine is a racemic mixture containing equal amounts of optical isomers that have almost identical pharmacokinetic properties but different pharmacodynamic effects. The S-(+)-isomer of ketamine has about twice the anaesthetic and analgesic potency of the racemic ketamine preparation and is judged to induce less psychic emergence reactions and to be followed by a more rapid recovery of vigilance. The present study was designed to assess whether the S-(+)-isomer of ketamine is superior to the racemic mixture in cardiovascular characteristics, emergence reactions and cognitive functions, and whether side effects may be reduced or prevented by administration of midazolam prior to injection of S-(+)-ketamine. METHODS. Following ethics committee approval and informed consent, 30 volunteers were randomly allocated in this double-blind study to three groups of 10 each. Group 1 received 2 mg/kg bw racemic ketamine, group 2, 1 mg/kg bw S-(+)-ketamine and group 3, 1 mg/kg bw S-(+)-ketamine after premedication with 0.1 mg/kg midazolam i.v. Cardiovascular changes, state of vigilance, cognitive performance, subjective mood and acceptance of anaesthesia were assessed by means of haemodynamic routine monitoring, electroencephalography (EEG), psychometric tests and interview. RESULTS. The increases in mean arterial pressure and heart rate following the injection of racemic ketamine and S-(+)-ketamine were identical and the differences from baseline values significant after both. Premedication with midazolam ensured stable haemodynamics after injection of S-(+)-ketamine. EEG analysis displayed the characteristic changes well known from ketamine anaesthesia for both racemic and S-(+)-ketamine. The vigilosomnoscript showed an identical profile of vigilance up to 30 min after injection of both drugs. The vigilance status after 125 min was less impaired by S-(+)-ketamine than by racemic ketamine. Psychological assessment showed a prompter recovery of visual attentiveness and sensorimotor performance in the S-(+)-ketamine group. Subjective mood was judged by the volunteers to be significantly better after S-(+)-ketamine, and volunteers found S-(+)-ketamine to be more acceptable than racemic ketamine. The frequency of dreams was the same after both drugs. No unpleasant dreams were reported after S-(+)-ketamine, but one of the volunteers who received racemic ketamine had uncomfortable dreams. Midazolam prevented any unpleasant emergence sequelae. On the other hand, the cognitive performance could not be restored to the baseline values until at least 240 min after injection of S-(+)-ketamine, because of the sedative effects of midazolam. DISCUSSION. These results suggest that S-(+)-ketamine offers the advantages of faster recovery of cognitive performance, greater acceptance by the volunteers and identical depth of anaesthesia after injection of half the dose compared with racemic ketamine. The clinical use of S-(+)-ketamine therefore seems to be justified. Premedication with benzodiazepines, e.g. midazolam, is essential. The dose to be administered, however, should be carefully selected in order not to abolish the positive effect of S-(+)-ketamine on vigilance by the sedative effects of the benzodiazepine.

Adult↗

PubMed1997

[Ketamine racemate and S-(+)-ketamine. Cerebrovascular effects and neuroprotection following focal ischemia].

The phencyclidine derivative ketamine is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist with the thalamo-neocortical projection system as the primary site of action. Racemic ketamine consists of the enantiomers S(+)-ketamine and R(-)-ketamine. Racemic ketamine has never been considered an adequate anaesthetic agent in neurosurgical patients since it produces regionally specific stimulation of cerebral metabolism (CMRO2) and increases cerebral blood flow (CBF) and intracranial pressure (ICP). However, recent experiments suggest that both tracemic ketamine and S(+)-ketamine may reduce infarct size in animal models of incomplete cerebral ischaemia and brain injury. This experimental protective effect appears to be related to decreases in Ca++ influx and maintenance of brain tissue magnesium levels due to NMDA and quisqualate receptor blockade by ketamine. Studies in dogs have shown that racemic ketamine (2.0 mg/kg) increases CBF in the presence of the cerebral vasodilator N2O. In contrast, studies in rats without background anaesthesia showed increases in CBF after racemic ketamine (100 mg/kg i.p.). This suggests that the cerebrovascular effects of racemic ketamine are related to the pre-existing cerebrovascular tone induced by background anaesthetics. Cerebrovascular CO2 reactivity was maintained regardless of the baseline cerebrovascular resistance. There are several mechanisms by which racemic ketamine may increase CBF. It induces dose-dependent respiratory depression with consequent mild hypercapnia in spontaneously ventilating subjects. This produces vasodilation due to the intact cerebrovascular CO2 reactivity. Racemic ketamine also induces regional neuroexcitation, which leads to stimulation of cerebral glucose consumption in the limbic, extrapyramidal, auditory, and sensory-motor systems. This regional neuroexcitation with increased CMRO2 produces increases in CBF that can be blocked by infusion of barbiturates or benzodiazepines. However, increases in CBF with racemic ketamine (1 mg/kg) may also occur during normocapnia and without changes in CMRO2. This effect is related to some additional direct cerebral vasodilating potency of racemic ketamine based on a mechanism involving blockade of Ca++ channels. The effects of racemic ketamine on CBF autoregulation have not been investigated systematically. However, studies in rats have shown that CBF autoregulation was maintained with low- and high-dose S(+)-ketamine. Infusion of racemic ketamine alters intracranial volume and ICP. Studies in spontaneously ventilating pigs with and without intracranial hypertension have shown that racemic ketamine (0.5-5.0 mg/kg) produces increases in PaCO2 and ICP. In contrast, identical experiments with mechanical ventilation and controlled PaCO2 showed no changes in ICP following racemic ketamine infusion. This implies that increases in ICP are related to inadequate ventilation with consecutive hypercapnia and increases in intracranial blood volume. However, mechanical ventilation may not be sufficient to control ICP following racemic ketamine. Experiments in mechanically ventilated dogs indicate that racemic ketamine (2 mg/kg) increases cerebral blood volume and ICP even in the presence of normoventilation, a response that is reversible by hyperventilation or the administration of diazepam. Studies in patients have shown that racemic ketamine (2.0 mg/kg) reduces CBF in the presence of cerebral vasodilators like halothane or N2O. In contrast, studies in unanaesthetised humans showed increases in CBF after racemic ketamine (2-3 mg/kg). This observation is consistent with animal studies and suggests that the cerebrovascular effects of racemic ketamine are related to the pre-existing cerebrovascular tone induced by background anaesthetics. Studies in humans with and without intracranial pathology confirm the data from animal experiments. (ABSTRACT TRUNCATED)

Animals↗

PubMed1994

[Psychometric changes as well as analgesic action and cardiovascular adverse effects of ketamine racemate versus s-(+)-ketamine in subanesthetic doses].

The intravenous anaesthetic ketamine is widely used in subanaesthetic doses as a potent analgesic in emergency and disaster medicine. At present, ketamine is commercially available only in its racemic form, although the S(+)-isomer has proved to be approximately three times as potent than the R(-)-isomer. In first clinical trials in Germany, S(+)-ketamine was reported to be markedly advantageous with regard to analgesia in anaesthetized patients. We therefore evaluated ketamine's analgesic and psychotropic effects in subanaesthetic doses given to healthy volunteers. MATERIALS AND METHODS. After institutional approval of the study by the university's Ethics Committee, 16 volunteers received ketamine racemate (1 mg/kg) and S(+)-ketamine (0.5 mg/kg) i.m. with 1-week intervals between injections in a randomized, double-blind fashion. Analgesia (electric pain stimulation of the median nerve), long-term memory, anterograde amnesia (recognition of simple pictures), motor coordination (Trieger test), immediate recall (short test of general intelligence) and concentration capacity (CI test: recognition of a preselected symbol among several symbols) were measured over a 60-min period and mean arterial pressure, heart rate, and ketamine plasma levels in venous blood samples were determined. Values were calculated as means and data were analysed by Wilcoxon's paired test for group comparison. RESULTS. Within 15 min, both agents induced a measurable degree of analgesia. After ketamine racemate, the level of pain tolerated increased from 38.8 +/- 14.0 to 57.0 +/- 13.7 mA and after S(+)-ketamine, from 36.9 +/- 10.5 to 53.3 +/- 15.2 mA. Ketamine racemate did not exert measurable effects on long-term memory, whereas anterograde amnesia was observed in 46% and 54% of the study subjects after 15 and 30 min, respectively. However, after S(+)-ketamine, only 8% of the volunteers demonstrated anterograde amnesia (P < 0.05). Immediate recall also declined in both groups (baseline: 5 points, after 15 min: 3.5 points for ketamine racemate, 4 points for S(+)-ketamine), whereas concentration capacity worsened from 14.5 +/- 3.8 s to 35.9 +/- 18.6 s after ketamine racemate and significantly less, from 14.8 +/- 2.5 s to 22.9 +/- 7.6 s, after S(+)-ketamine (P < 0.01). Furthermore, after 15 min, ketamine racemate induced an increase in heart rates from 73 +/- 15 b/min to 97 +/- 11 b/min, while S(+)-ketamine raised heart rates from 74 +/- 13 b/min to 89 +/- 11 b/min only (P < 0.05). Mean arterial pressure increased from 97 +/- 11 mmHg to 111 +/- 9 mmHg after ketamine racemate and from 92 +/- 11 mmHg to 110 +/- 13 mmHg after S(+)-ketamine (not significantly different). CONCLUSION. S(+)-Ketamine at half-dose of ketamine-racemate is as potent as ketamine-racemate in subanaesthetic doses with powerful analgesic properties. The (+)-isomer exerts less adverse effects on measurable cerebral functions and induces a significantly smaller increase in heart rate. Since states of impaired consciousness and disorientation are especially disturbing under emergency conditions, further investigations should be carried out to define S(+)-ketamine's position as a potent analgesic for therapeutic use in emergency and disaster medicine.

Adult↗

PubMed2005

Comparison of psychic emergence reactions after (+/-)-ketamine and (+)-ketamine in mice.

Ketamine is a racemic mixture containing equal parts of (+)-ketamine and (-)-ketamine. The ketamine enantiomorphs are different in anesthesia and psychic emergence reactions after anesthesia. Therefore, (+)-ketamine was compared with racemic ketamine in a number of randomized studies in volunteers and patients. However, their relations remain controversial. In the present studies, the psychic emergence reactions after injection of (+/-)-ketamine and (+)-ketamine were compared in mice. At equimolar doses, the (+)-isomers elicited episodes of hypnosis nearly 1.4-fold more potent than those of the racemic ketamine. After the administration of equihypnotic doses of (+)-ketamine and (+/-)-ketamine, the posthypnotic stimulation of locomotor activity, stereotype behavior and 5-HT-induced head-twitch response by the (+)-enantiomorph was significantly less intense than that of racemic ketamine. In receptor binding test, (+)-ketamine showed a higher affinity for NMDA receptor than that of (+/-)-ketamine, while (+)-ketamine and (+/-)-ketamine showed no affinity for dopamine D2 and serotonin 5-HT2 receptor. These results suggest that the (+)-ketamine has fewer posthypnotic side effects than (+/-)-ketamine when (+)-ketamine and (+/-)-ketamine were administered at equihypnotic dosages and that dopamine D2 and serotonin 5-HT2 receptor were not involved in the effects of (+)-ketamine and (+/-)-ketamine.

Anesthetics, Dissociative↗

PubMed1993

[Acoustic evoked potentials of medium latency. Anesthesia induction with S-(+)-ketamine versus ketamine racemate].

Mid-latency auditory evoked potentials (MLAEP) reflect the primary cortical processing of auditory stimuli. They are widely suppressed during general anaesthesia with volatile anaesthetics. Under ketamine, in contrast, they seem to be preserved, which has been interpreted as indicating insufficient suppression of consciousness during ketamine anaesthesia. Ketamine exists in two optical isomeres, S-(+)-ketamine und R-(-)-ketamine, which differ in their pharmacodynamic properties: S-(+)-ketamine has higher anaesthetic-hypnotic and analgesic potency than R-(-)-ketamine. It thus appears obvious to question whether S-(+)-ketamine has a different effect on the primary cortical processing of sensory, i.e., auditory stimuli. We therefore studied the effects of S-(+)-ketamine versus ketamine-racemate on MLAEP. PATIENTS AND METHODS. Institutional approval and informed consent were obtained for 40 patients scheduled for minor gynaecological procedures. The patients were assigned randomly to one of the two experimental groups. All experimental evaluations were conducted under double-blind conditions. Anaesthesia was induced with S-(+)-ketamine 1 mg/kg (group I, n = 20) or ketamine-racemat 2 mg/kg (group II, n = 20). MLAEP were recorded before, during, and after induction of general anaesthesia from the vertex (positive) and mastoids on both sides (negative). Auditory clicks were presented binaurally at 70 dBnHL at a rate of 9.3 Hz. Using the electrodiagnostic system Pathfinder I (Nicolet), 1000 successive stimulus responses were averaged over a 100-ms poststimulus interval and analysed off-line. Latencies of the peak V, Na, Pa, Nb, P1, N1, and amplitudes Na/Pa, Pa/Nb, and Nb/P1 were measured. V belongs to the brainstem-generated potentials, which demonstrates that auditory stimuli were correctly transduced. Na, Pa, Nb, P1, and N1 are generated in the primary auditory cortex of the temporal lobe and are the electrophysiological correlate of the primary cortical processing of the auditory stimuli. A Fast-Fourier transformation calculated powerspectra of the AEP. RESULTS. In the awake state, AEP peak latencies were in the normal range. MLAEP had high amplitudes and a periodic wave form. Powerspectra indicated high energy in the 30-40-Hz frequency range. After induction of general anaesthesia with (S+)-ketamine or ketamine-racemat, there was no increase in the latencies of the peaks V, Na, Pa, Nb, P1, and N1. No decrease in amplitudes Na/Pa, Pa/Nb, or Nb/P1 could be observed. In the power spectra, frequencies in the range of 30-40 Hz retained high energy. CONCLUSIONS. MLAEP do not change in amplitude or latency during induction of general anesthesia with S-(+)-ketamine or ketamine-racemat. Primary cortical processing of auditory stimuli seems to preserved under S-(+)-ketamine and ketamine-racemat. This must be viewed in connection with dreams and hallucinations and could be interpreted as inadequate suppression of auditory information processing during general anaesthesia with S-(+)-ketamine and ketamine-racemat.

Adult↗

PubMed1994

[Ketamine racemate versus S-(+)-ketamine with or without antagonism with physostigmine. A quantitative EEG study on volunteers].

The potency of S-(+)-ketamine is approximately double that of the racemic ketamine. This study was carried out to investigate the recovery of cerebral electrical function after a bolus of 1.3 mg/kg ketamine or 0.65 mg/kg S-(+)-ketamine and subsequent continuous application of 4 mg/kg h ketamine per h or 2 mg/kg S-(+)-ketamine, per h for 15 min. Furthermore, the centrally acting, cholinergic agonist physostigmine has been reported to antagonize ketamine and to shorten the recovery period. Therefore, after S-(+)-ketamine 0.012 mg/kg physostigmine was tested against saline placebo. METHODS. With their own informed consent and the approval of the ethics committee 12 healthy volunteers were enrolled in a double-blind cross-over study. All drugs were dissolved in identical volumes. On three dates with intervals of at least 1 week between, ketamine/NaCl, S-(+)-ketamine/physostigmine or S-(+)-ketamine/NaCl was administered (Table 1). The sequence was randomized. The EEG was recorded from 20 sites according to the 10/20 system and after Fast-Fourier transformation computed into amplitudes within the delta, theta, alpha, and beta bands and within the total spectrum. The median, the spectral edge frequency and the dominant frequency (dF) were also determined. Mean values of all electrodes before and at 10, 15, 30, 45 and 195 min after the bolus injection were compared using two-dimensional analysis of variance (ANOVA, significance level P < 0.05). RESULTS. The characteristic increase in theta-amplitude and decrease of alpha-amplitude were observed after ketamine and S-(+)-ketamine. Median and dF dropped from the alpha to the theta frequency range. Ketamine led to a greater increase in total, delta, theta and beta amplitude during anaesthesia. 3 hours after ketamine/S-(+)-ketamine anaesthesia a significant decrease in the median and dominant frequency and in total, delta, theta, alpha and beta amplitudes confirmed residual impairment of cerebral function after all study drugs. No differences were found between physostigmine and placebo. DISCUSSION. The EEG changes during ketamine/S-(+)-ketamine administration suggest a slightly deeper anaesthetic level after ketamine. The course of recovery was not different after ketamine and after S-(+)-ketamine. The spectral edge frequency did not differ between measurement points, and is therefore not suitable for assessment of the depth of anaesthesia reached with ketamine/S-(+)-ketamine. The dose of physostigmine tested was probably too low to produce antagonism of S-(+)-ketamine. An increased dosage of physostigmine has yet to be studied, but is likely to cause a higher rate of side effects, such as nausea, vomiting and bradycardia, and possibly even tonic-clonic seizures.

Adolescent↗

PubMed2002

Cognitive impairment after small-dose ketamine isomers in comparison to equianalgesic racemic ketamine in human volunteers.

BACKGROUND: Ketamine is increasingly used in pain therapy but may impair brain functions. Mood and cognitive capacities were compared after equianalgesic small-dose S(+)-, R(-)-, and racemic ketamine in healthy volunteers. METHODS: Twenty-four subjects received intravenous 0.5 mg/kg racemic, 0.25 mg/kg S(+)-, and 1.0 mg/kg R(-)-ketamine in a prospective, randomized, double-blind, crossover study. Hemodynamic variables, mood, and cognitive capacities were assessed for 60 min. RESULTS: Transient increases in blood pressure, heart rate, and catecholamines were similar after administration of all drugs. At 20 min after injection, subjects felt less decline in concentration and were more brave after S(+)- than racemic ketamine. They reported being less lethargic but more out-of-control after R(-)- than racemic ketamine. Ketamine isomers induced less drowsiness, less lethargy, and less impairment in clustered subjective cognitive capacity than racemic ketamine for the 60-min study. Objective concentration capacity [test time, S(+): 25.4 +/- 15.2 s, R(-): 34.8 +/- 18.4 s, racemic ketamine: 40.8 +/- 20.8 s, mean +/- SD] and retention in primary memory [test time, S(+): 4.6 +/- 1.2 s, R(-): 4.2 +/- 1.4 s, racemic ketamine: 4.0 +/- 1.4 s, mean +/- SD] declined less after S(+)- than either R(-)- or racemic ketamine at 1 min. At 5 min, immediate recall, anterograde amnesia, retention in primary memory, short-term storage capacity, and intelligence quotient were less reduced after the isomers than racemic ketamine. Speed reading and central information flow decreased less after S(+)- than racemic ketamine. CONCLUSIONS: Early after injection, ketamine isomers induce less tiredness and cognitive impairment than equianalgesic small-dose racemic ketamine. In addition, S(+)-ketamine causes less decline in concentration capacity and primary memory. The differences in drug effects cannot be explained by stereoselective action on one given receptor.

Adult↗

PubMed1994

Mid-latency auditory evoked potentials in humans during anesthesia with S (+) ketamine--a double-blind, randomized comparison with racemic ketamine.

Mid-latency auditory evoked potentials (MLAEP) reflect the primary cortical processing of auditory stimuli. They are suppressed widely during general anesthesia. Under ketamine, in contrast, MLAEP seem to be preserved. Ketamine exists in two optical isomers, S (+) ketamine and R (-) ketamine, which differ in their pharmacodynamic properties. S (+) ketamine has a higher anesthetic-hypnotic and analgesic potency than R (-) ketamine or the racemic mixture of S (+) ketamine and R (-) ketamine. In a blinded, randomized evaluation we compared the effect of induction of general anesthesia with the more potent ketamine compound--S (+) ketamine--to induction with the racemic ketamine on MLAEP in 60 patients scheduled for minor gynecologic procedures. Anesthesia was induced with S (+) ketamine (1 mg/kg Group I, n = 30) or an equi-anesthetic dose of racemic ketamine (2 mg/kg, Group II, n = 30). Auditory evoked potentials (AEP) were recorded before, during, and after induction of general anesthesia. Latencies of the peaks V, Na, Pa, Nb, and P1 and amplitudes Na/Pa, Pa/Nb, and Nb/P1 were measured. A fast-Fourier transform was used to calculate the power spectra of the AEP. The baseline MLAEP peaks of the awake patients were of normal amplitude and demonstrated a characteristic periodic wave form morphology. Power spectra indicated high energy in the 30-40 Hz frequency range. After induction of general anesthesia with S (+) ketamine or racemic ketamine, there was no increase in latencies of peaks V, Na, Pa, Nb, or P1. No decrease in amplitudes Na/Pa, Pa/Nb, or Nb/P1 could be observed. There was no significant change in the power spectra.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed2003

Plasma concentration profiles of ketamine and norketamine after administration of various ketamine preparations to healthy Japanese volunteers.

Ketamine is known to provide analgesic effects without an anesthetic when administered in a low dose. We previously reported that a tablet containing ketamine had analgesic effects in patients with neuropathic pain. In the present study, we compared the plasma concentration profiles of the enantiomers of ketamine and its active metabolite, norketamine, up to 8 h after the administration of 20 mg of ketamine by injection, after the administration of two tablets containing 25 mg of ketamine, after the administration of two sublingual tablets containing 25 mg of ketamine, after the insertion of a suppository containing 50 mg of ketamine, and after the application of a nasal spray containing 25 mg of ketamine to three healthy volunteers. The plasma concentration of ketamine biexponentially declined after the administration by injection; the value of T(1/2beta) for ketamine was approximately 120 min. The bioavailability of the tablet was estimated to be approximately 20%; the area under the plasma concentration-time curve, (AUC)(0-->8 h), of norketamine was approximately 500 ng h/ml in both enantiomers. The bioavailabilities of the sublingual tablet and the suppository were estimated to both be approximately 30%; the AUC(0-->8 h) of norketamine was 280-460 ng h/ml in both enantiomers. The plasma concentration profiles of the sublingual tablet and the suppository were almost similar to that of the tablet. The bioavailability of the nasal spray was estimated to be approximately 45%, which was the highest value among the preparations tested, and the AUC(0-->6 h) of norketamine was low (approximately 100 ng h/ml) in both enantiomers. These pharmacokinetic findings suggested that all of the ketamine preparations tested in this study may be useful for the alleviation of neuropathic pain. We propose that the type of ketamine preparation should be selected in accordance with the patient's disease condition and the required dosage amount of ketamine.

Administration, Intranasal↗

PubMed1998

[Recovery time after (S)-ketamine or ketamine racemate. Recovery time after short anesthesia in volunteers].

UNLABELLED: The anaesthetic potency of the (S)-ketamine isomer is approximately double that of racemic ketamine. The aim of this study was to compare the recovery of cerebral function after a bolus of 1.3 mg/kg racemic ketamine or 0.65 mg/kg (S)-ketamine followed by continuous application of 4 or 2 mg/kg x h over 15 minutes. METHODS: With their informed consent and approval of the local ethics committee 12 healthy volunteers were enrolled in a double-blind, cross-over study. All drugs were dissolved in identical volumes. On three dates with an interval of one week at least ketamine/NaCl, (S)-ketamine/physostigmine or (S)-ketamine/NaCl was administered (table 1). The sequence was randomized. In addition, the unspecific antagonistic potential of the centrally acting, cholinergic agonist physostigmine (0.012 mg/kg) after (S)-ketamine was tested against saline-placebo. Neuropsychological tests (tests 3-5 of the syndrome-short-test [Erzigkeit, see references]) were used to quantify cerebral function before and at 45, 75, 105, 135, 165 and 195 min after anaesthesia. All data are mean values and standard deviation. Comparisons over time and between drugs were carried out using two-dimensional analysis of variance (ANOVA). Wilcoxon-tests were used post-hoc. p < 0.05 was considered significant. RESULTS: After (S)-ketamine the subjects were able to carry out the tasks more rapidly than after racemic ketamine (p < 0.05). Mean time to reach preoperative test performance +10% was 117.5 min for (S)-ketamine/physostigmine, 121.3 min for (S)-ketamine/NaCl and 141.6 min for racemic ketamine (p < 0.05 between (S)-ketamine and racemic ketamine). No differences were found between physostigmine and placebo. The incidence of side effects (mainly nausea, vomiting) was not different. DISCUSSION: (S)-ketamine offers a shorter recovery time after short anaesthesia compared to racemic ketamine. The investigated dose of physostigmine was probably too low to produce antagonism of (S)-ketamine. An increased dosage of physostigmine has yet to be studied, but is likely to cause a higher rate of side effects such as nausea, vomiting, bradycardia and possibly even tonic-clonic seizures.

Adult↗

PubMed2004

The effects of S+-ketamine and racemic ketamine on uterine blood flow in chronically instrumented pregnant sheep.

UNLABELLED: Ketamine could be a useful maternal analgesic in obstetric surgery, as it might avoid the need for opioid administration and associated side effects in the newborn. Racemic ketamine passes the placental barrier and has oxytocin-like properties but does not seem to affect uterine blood flow (UBF). S(+)-ketamine was recently approved for clinical use, but its effects on UBF have not been evaluated. Therefore, we studied the effects of S(+)-ketamine on maternal and fetal hemodynamic variables. Equianalgesic doses of S(+)-ketamine (10 mg.kg(-1).h(-1)) or racemic ketamine (20 mg.kg(-1).h(-1)) were infused in 12 chronically instrumented pregnant sheep. Maternal and fetal vital signs, blood gases, and UBF were recorded over 120 min. Neither compound affected uterine perfusion or maternal and fetal hemodynamics. Whereas racemic ketamine increased maternal (+19%) and fetal (+11%) PCO(2) significantly, S(+)-ketamine was without effect. However, both compounds significantly decreased maternal (racemic, -0.05; S(+), -0.03) and fetal (racemic, -0.06; S(+), -0.02) pH. The effects of racemic ketamine and S(+)-ketamine on uterine perfusion are similar, and because of its limited effect on hemodynamics and respiration, S(+)-ketamine might therefore be of interest as an analgesic in the obstetric setting. IMPLICATIONS: The effects of S(+)-ketamine on uterine perfusion and maternal/fetal hemodynamics are similar to those of the racemic mixture in chronically instrumented pregnant sheep. A decreased effect of S(+)-ketamine, as compared with the racemic mixture, on maternal and fetal PCO(2) levels was noted.

Acid-Base Equilibrium↗

PubMed2006

Roadside detection of impairment under the influence of ketamine--evaluation of ketamine impairment symptoms with reference to its concentration in oral fluid and urine.

Although there are many roadside testing devices available for the screening of abused drugs, none of them can be used for the detection of ketamine, a popular abused drug in Hong Kong. In connection to local drug driving legislation, effective roadside detection of ketamine in suspected drug-impaired drivers has to be established. According to the drug evaluation and classification program (DEC), ketamine is classified in the phencyclidine (PCP) category. However, no study has been performed regarding the signs and symptoms exhibited by users under the influence of ketamine. In a study to develop a protocol for effective roadside detection of drug-impaired drivers, 62 volunteers exiting from discos were assessed using field impairment tests (FIT) that included measurements of three vital signs (i.e. body temperature, pulse rate and blood pressure), three eye examinations [pupil size, lack of convergence (LOC) and horizontal gaze nystagmus (HGN)] and four divided attention tests (Romberg, one-leg stand, finger-to-nose and walk-and-turn tests). Subsequent laboratory analysis of oral fluid and urine samples from the participants revealed the presence of common abused drugs in both the urine and oral fluid samples of 55 subjects. The remaining 7 subjects with no drug in their oral fluid samples were used as drug-free subjects. In addition, 10 volunteers from the laboratory who were regarded as drug-free subjects were also assessed using the same FIT. Among the 62 volunteers, 39 of them were detected with ketamine in their oral fluid. Of these ketamine users, 21 of them (54%) with only ketamine found in their oral fluid samples while the rest (18 subjects) of them had other drugs (i.e. MA, MDMA, benzodiazepines and/or THC) in addition to ketamine. Of the 21 ketamine-only users, 15 of them (71%) were successfully identified by FIT. It was found that when salivary ketamine concentrations were greater than 300 ng/mL, signs of impairment became evident, with over 90% detection rate using the FIT. By comparing the FIT observations on the 21 ketamine-only users with the drug-free subjects, the typical signs and symptoms observable for subjects under the influence of ketamine included LOC, HGN, elevated pulse rate and in general, failing the divided attention tests, especially the walk-and-turn and one-leg stand.

Adult↗